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Circulating Tumor DNA as a Biomarker for Monitoring Patients with Solid Cancers: Comparison with Standard Protein Biomarkers Clin. Chem. (IF 12.167) Pub Date : 2022-08-13 Michael J Duffy, John Crown
Background Protein-based biomarkers are widely used in monitoring patients with diagnosed cancer. These biomarkers however, lack specificity for cancer and have poor sensitivity in detecting early recurrences and monitoring therapy effectiveness. Emerging data suggest that the use of circulating tumor DNA (ctDNA) has several advantages over standard biomarkers. Content Following curative-intent surgery
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Differences between Educational and Regulatory External Quality Assurance/Proficiency Testing Schemes. Clin. Chem. (IF 12.167) Pub Date : 2022-08-12 Tony Badrick,Graham Jones,W Greg Miller,Mauro Panteghini,Andrew Quintenz,Sverre Sandberg,Michael Spannagl
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Targeting FAPα-expressing hepatic stellate cells overcomes resistance to anti-angiogenics in colorectal cancer liver metastasis models. J. Clin. Invest. (IF 19.456) Pub Date : 2022-08-11 Ming Qi,Shuran Fan,Maohua Huang,Jinghua Pan,Yong Li,Qun Miao,Wenyu Lyu,Xiaobo Li,Lijuan Deng,Shenghui Qiu,Tongzheng Liu,Weiqing Deng,Xiaodong Chu,Chang Jiang,Wenzhuo He,Liangping Xia,Yunlong Yang,Jian Hong,Qi Qi,Wenqian Yin,Xiangning Liu,Changzheng Shi,Minfeng Chen,Wencai Ye,Dongmei Zhang
Vessel co-option has been demonstrated to mediate colorectal cancer liver metastasis (CRCLM) resistance to anti-angiogenic therapy. The current mechanisms underlying vessel co-option have mainly focused on the "hijacker" tumor cells, whereas the function of the "hijackee" sinusoidal blood vessels has not been explored. Here, we found that the occurrence of vessel co-option in bevacizumab-resistant
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In vivo visualization and molecular targeting of the cardiac conduction system. J. Clin. Invest. (IF 19.456) Pub Date : 2022-08-11 William R Goodyer,Benjamin M Beyersdorf,Lauren Duan,Nynke S van den Berg,Sruthi Mantri,Francisco X Galdos,Nazan Puluca,Jan W Buikema,Soah Lee,Darren Salmi,Elise R Robinson,Stephan Rogalla,Dillon P Cogan,Chaitan Khosla,Eben L Rosenthal,Sean M Wu
Accidental injury to the cardiac conduction system (CCS), a network of specialized cells embedded within the heart and indistinguishable from the surrounding heart muscle tissue, is a major complication in cardiac surgeries. Here, we addressed this unmet need by engineering targeted antibody-dye conjugates directed against CCS, allowing for the visualization of the CCS in vivo following a single intravenous
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Impaired renal reserve contributes to preeclampsia via the kynurenine and soluble fms-like tyrosine kinase 1 pathway. J. Clin. Invest. (IF 19.456) Pub Date : 2022-08-09 Vincent Dupont,Anders H Berg,Michifumi Yamashita,Chengqun Huang,Ambart E Covarrubias,Shafat Ali,Aleksandr Stotland,Jennifer E Van Eyk,Belinda Jim,Ravi Thadhani,S Ananth Karumanchi
To understand how kidney donation leads to excess preeclampsia risk, we studied pregnant outbred mice with prior uninephrectomy and compared them to sham-treated littermates carrying both kidneys. During pregnancy, uninephrectomized mice failed to achieve physiological increase of glomerular filtration rate, and during late gestation developed hypertension, albuminuria, glomerular endothelial damage
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An Update on Laboratory-Based Diagnostic Biomarkers for Multiple Sclerosis and Beyond. Clin. Chem. (IF 12.167) Pub Date : 2022-08-08 Ruba S Saadeh,Paola A Ramos,Alicia Algeciras-Schimnich,Eoin P Flanagan,Sean J Pittock,Maria Alice Willrich
BACKGROUND Multiple sclerosis (MS) is an immune-mediated central nervous system (CNS) inflammatory demyelinating disease in which analysis of clinical presentation, imaging studies, and laboratory tests aid in diagnosis. CONTENT This review discusses laboratory tests ordered to rule out and rule in MS, such as the traditional measurement of cerebrospinal fluid (CSF) IgG index and oligoclonal bands
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Assays Specific for BNP1-32 and NT-proBNP Exhibit a Similar Performance to Two Widely Used Assays in the Diagnosis of Heart Failure Clin. Chem. (IF 12.167) Pub Date : 2022-08-06 Lynley K Lewis, Sara D Raudsepp, Joanna C Whitlow, Sarah Appleby, Christopher J Pemberton, Timothy G Yandle, A Mark Richards
Background Secretion of cardioprotective B-type natriuretic peptide 1–32 (BNP1-32) is increased proportionately with cardiac dysfunction, but its measurement in plasma is difficult. Therefore, less specific BNP and amino-terminal proBNP (NT-proBNP) assays that detect the precursor molecule proBNP alongside BNP or NT-proBNP metabolites were developed to reflect BNP1-32 secretion and are now mandated
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Cell-Free RNA Transcriptome and Prediction of Adverse Pregnancy Outcomes. Clin. Chem. (IF 12.167) Pub Date : 2022-08-05 Kathryn J Gray,Martin Hemberg,S Ananth Karumanchi
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Effect of Macrotroponin in a Cohort of Community Patients with Elevated Cardiac Troponin Clin. Chem. (IF 12.167) Pub Date : 2022-08-05 Leo Lam, Rexson Tse, Patrick Gladding, Campbell Kyle
Background Macrotroponin is an important cause of discrepancy between current high-sensitivity cardiac troponin (hs-cTn) assays, however, its clinical significance is unclear. This study examined the effects of macrotroponin and repeat testing by different hs-cTnI assays in a cohort of community patients with elevated hs-cTnI. Methods The first residual serum specimen from each patient in the community
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Relieving Dyrk1a repression of MKL1 confers an adult-like phenotype to human infantile megakaryocytes. J. Clin. Invest. (IF 19.456) Pub Date : 2022-08-04 Kamaleldin E Elagib,Ashton Brock,Cara M Clementelli,Gohar Mosoyan,Lorrie L Delehanty,Ranjit K Sahu,Alexandra Pacheco-Benichou,Corinne Fruit,Thierry Besson,Stephan W Morris,Koji Eto,Chintan Jobaliya,Deborah L French,Paul Gadue,Sandeep Singh,Xinrui Shi,Fujun Qin,Robert Cornelison,Hui Li,Camelia Iancu-Rubin,Adam N Goldfarb
Infantile (fetal and neonatal) megakaryocytes have a distinct phenotype consisting of hyperproliferation, limited morphogenesis, and low platelet production capacity. These properties contribute to clinical problems that include thrombocytopenia in neonates, delayed platelet engraftment in recipients of cord blood stem cell transplants, and inefficient ex vivo platelet production from pluripotent stem
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Breast cancer cell-derived microRNA-155 suppresses tumor progression via enhancing immune cell recruitment and anti-tumor function. J. Clin. Invest. (IF 19.456) Pub Date : 2022-08-04 Junfeng Wang,Quanyi Wang,Yinan Guan,Yulu Sun,Xiaozhi Wang,Kaylie Lively,Yuzhen Wang,Ming Luo,Julian A Kim,E Angela Murphy,Yongzhong Yao,Guoshuai Cai,Daping Fan
Evidence suggests that increased microRNA-155 (miR-155) expression in immune cells enhances anti-tumor immune responses. However, given the reported association of miR-155 to tumorigenesis in various cancers, a debate is provoked on whether miR-155 is oncogenic or tumor suppressive. We aimed to interrogate the impact of tumor miR-155 expression, particularly cancer cell-derived miR-155, on anti-tumor
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Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells J. Clin. Invest. (IF 19.456) Pub Date : 2022 Peng Wang, Esra Karakose, Carmen Argmann, Huan Wang, Metodi Balev, Rachel I. Brody, Hembly G. Rivas, Xinyue Liu, Olivia Wood, Hongtao Liu, Lauryn Choleva, Dan Hasson, Emily Bernstein, Joao A. Paulo, Donald K. Scott, Luca Lambertini, James A. DeCaprio, Andrew F. Stewart
Resistance to regeneration of insulin-producing pancreatic β cells is a fundamental challenge for type 1 and type 2 diabetes. Recently, small molecule inhibitors of the kinase DYRK1A have proven effective in inducing adult human β cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and β cell transcriptomic databases seeking
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Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer J. Clin. Invest. (IF 19.456) Pub Date : 2022 He Huang, Cai-ping Nie, Xiu-feng Liu, Bin Song, Jian-hui Yue, Jing-xiao Xu, Jia He, Kui Li, Yan-ling Feng, Ting Wan, Min Zheng, Yan-Na Zhang, Wei-Jun Ye, Jun-Dong Li, Yan-Fang Li, Jun-yun Li, Xin-Ping Cao, Zhi-min Liu, Xiao-shi Zhang, Qing Liu, Xi Zhang, Ji-Hong Liu, Jiang Li
BACKGROUND. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has achieved remarkable clinical efficacy in metastatic cancers such as melanoma and cervical cancer (CC). Here, we explored the safety, feasibility, and preliminary tumor response and performed translational investigations of adjuvant immunotherapy using infusion of autogenous TILs (auto-TILs) following concurrent chemoradiotherapy
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Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression J. Clin. Invest. (IF 19.456) Pub Date : 2022 Emilia A. Korhonen, Aino Murtomäki, Sawan Kumar Jha, Andrey Anisimov, Anne Pink, Yan Zhang, Simon Stritt, Inam Liaqat, Lukas Stanczuk, Laura Alderfer, Zhiliang Sun, Emmi Kapiainen, Abhishek Singh, Ibrahim Sultan, Anni Lantta, Veli-Matti Leppänen, Lauri Eklund, Yulong He, Hellmut G. Augustin, Kari Vaahtomeri, Pipsa Saharinen, Taija Mäkinen, Kari Alitalo
Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor 3 (VEGFR3), which is encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development, and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, the mechanistic basis of Ang2 activity in
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Repeated exposure to heterologous hepatitis C viruses associates with enhanced neutralizing antibody breadth and potency J. Clin. Invest. (IF 19.456) Pub Date : 2022 Nicole Frumento, Alexis Figueroa, Tingchang Wang, Muhammad N. Zahid, Shuyi Wang, Guido Massaccesi, Georgia Stavrakis, James E. Crowe Jr, Andrew I. Flyak, Hongkai Ji, Stuart C. Ray, George M. Shaw, Andrea L. Cox, Justin R. Bailey
A prophylactic hepatitis C virus (HCV) vaccine that elicits neutralizing antibodies could be key to HCV eradication. However, the genetic and antigenic properties of HCV envelope (E1E2) proteins capable of inducing anti-HCV broadly neutralizing antibodies (bNAbs) in humans have not been defined. Here, we investigated the development of bNAbs in longitudinal plasma of HCV-infected persons with persistent
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Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia J. Clin. Invest. (IF 19.456) Pub Date : 2022 José A. Casado, Antonio Valeri, Rebeca Sanchez-Domínguez, Paula Vela, Andrea López, Susana Navarro, Omaira Alberquilla, Helmut Hanenberg, Roser Pujol, José-Carlos Segovia, Jordi Minguillón, Jordi Surrallés, Cristina Díaz de Heredia, Julián Sevilla, Paula Rio, Juan A. Bueren
Fanconi anemia (FA) is the most prevalent inherited bone marrow failure (BMF) syndrome. Nevertheless, the pathophysiological mechanisms of BMF in FA have not been fully elucidated. Since FA cells are defective in DNA repair, we hypothesized that FA hematopoietic stem and progenitor cells (HSPCs) might express DNA damage–associated stress molecules such as natural killer group 2 member D ligands (NKG2D-Ls)
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GIGYF1 disruption associates with autism and impaired IGF-1R signaling. J. Clin. Invest. (IF 19.456) Pub Date : 2022-08-02 Guodong Chen,Bin Yu,Senwei Tan,Jieqiong Tan,Xiangbin Jia,Qiumeng Zhang,Xiaolei Zhang,Qian Jiang,Yue Hua,Yaoling Han,Shengjie Luo,Kendra Hoekzema,Raphael A Bernier,Rachel K Earl,Evangeline C Kurtz-Nelson,Michaela J Idleburg,Suneeta Madan Khetarpal,Rebecca Clark,Jessica Sebastian,Alberto Fernandez-Jaen,Sara Alvarez,Staci D King,Luiza Lp Ramos,Mara Lucia Sf Santos,Donna M Martin,Dan Brooks,Joseph D Symonds
Autism spectrum disorder (ASD) represents a group of neurodevelopmental phenotypes with a strong genetic component. Excess of likely gene-disruptive (LGD) mutations of GIGYF1 was implicated in ASD. Here, we reported that GIGYF1 was the second most mutated gene among known ASD high-confidence risk genes. We investigated the inheritance of 46 GIGYF1 LGD variants, including the highly recurrent mutation
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A Targeted Liquid Chromatography–Tandem Mass Spectrometry Method for Simultaneous Quantification of Peptides from the Carboxyl-terminal Region of Type III Procollagen, Biomarkers of Collagen Turnover Clin. Chem. (IF 12.167) Pub Date : 2022-07-30 Huu-Hien Huynh, Katrina Forrest, Jessica O Becker, Michelle A Emrick, Geoffrey D Miller, Danielle Moncrieffe, David A Cowan, Andreas Thomas, Mario Thevis, Michael J MacCoss, Ben Hoffstrom, Peter H Byers, Daniel Eichner, Andrew N Hoofnagle
Background The development of analytical approaches to help reduce the risk of growth hormone (GH) doping is important to fair competition and the health of athletes. However, the reliable detection of GH use remains challenging. The identification of novel biomarkers of GH administration could lead to a better understanding of the physiological response to GH, more sensitive detection of the illicit
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Diabetes Duration and Subclinical Myocardial Injury: The Atherosclerosis Risk in Communities Study (ARIC) Clin. Chem. (IF 12.167) Pub Date : 2022-07-29 Carine E Hamo, Justin B Echouffo-Tcheugui, Sui Zhang, Roberta Florido, James S Pankow, Erin D Michos, Ronald Goldberg, Vijay Nambi, Gary Gerstenblith, Wendy S Post, Roger S Blumenthal, Christie Ballantyne, Elizabeth Selvin, Josef Coresh, Chiadi E Ndumele
Background Diabetes exerts adverse effects on the heart, and a longer diabetes duration is associated with greater heart failure risk. We studied diabetes duration and subclinical myocardial injury, as reflected by high-sensitivity cardiac troponin (hs-cTnT). Methods We analyzed 9052 participants without heart failure or coronary heart disease (mean age 63 years, 58% female, 21% Black, 15% with diabetes)
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SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-28 Museer A Lone,Mari J Aaltonen,Aliza Zidell,Helio F Pedro,Jonas A Morales Saute,Shalett Mathew,Payam Mohassel,Carsten G Bonnemann,Eric A Shoubridge,Thorsten Hornemann
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Mutations in the SPTLC1 subunit of serine-palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity. We show
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Small molecule eRF3a degraders rescue CFTR nonsense mutations by promoting premature termination codon readthrough. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-28 Rhianna E Lee,Catherine A Lewis,Lihua He,Emily C Bulik-Sullivan,Samuel C Gallant,Teresa M Mascenik,Hong Dang,Deborah M Cholon,Martina Gentzsch,Lisa C Morton,John T Minges,Jonathan W Theile,Neil A Castle,Michael R Knowles,Adam J Kimple,Scott H Randell
The vast majority of people with cystic fibrosis (CF) are now eligible for CF transmembrane regulator (CFTR) modulator therapy. Remaining individuals harbor premature termination codons (PTCs) or rare CFTR variants with limited treatment options. Although clinical modulator response can be reliably predicted using primary airway epithelial cells, primary cells carrying rare CFTR variants are scarce
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Bone marrow confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-28 Yang Mei,Kehan Ren,Yijie Liu,Annabel Ma,Zongjun Xia,Xu Han,Ermin Li,Hamza Tariq,Haiyan Bao,Xinshu Xie,Cheng Zou,Dingxiao Zhang,Zhaofeng Li,Lili Dong,Amit Verma,Xinyan Lu,Yasmin Abaza,Jessica K Altman,Madina Sukhanova,Jing Yang,Peng Ji
Myelodysplastic syndromes (MDS) are age-related myeloid neoplasms with increased risks of progression to acute myeloid leukemia (AML). The mechanisms of MDS to AML transformation are poorly understood, especially in relation to the aging microenvironment. We previously established a mDia1/miR-146a double knockout (DKO) mouse model phenocopying MDS. These mice develop age-related pancytopenia with over-secretion
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Assessment of LDL-C Calculation Using the Newly Adopted NIH LDL-C Equation in a Pediatric Population. Clin. Chem. (IF 12.167) Pub Date : 2022-07-28 Ka Keung Chan,Jane A Dickerson
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Cardiac Troponin as a Marker of Heart Failure Risk in Diabetes. Clin. Chem. (IF 12.167) Pub Date : 2022-07-28 Eric S Kilpatrick
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Estimated Atherosclerotic Cardiovascular Disease Risk Score: An Automated Decision Aid for Statin Therapy Clin. Chem. (IF 12.167) Pub Date : 2022-07-28 Maureen Sampson, Anna Wolska, Marcelo Amar, Masako Ueda, Richard Dunbar, Daniel Soffer, Alan T Remaley
Background Estimation of atherosclerotic cardiovascular disease (ASCVD) risk is a key step in cardiovascular disease (CVD) prevention, but it requires entering additional risk factor information into a computer. We developed a simplified ASCVD risk score that can be automatically calculated by the clinical laboratory when a fasting standard lipid panel is reported. Methods Equations for an estimated
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Macrotroponin Complex as a Cause for Cardiac Troponin Increase after COVID-19 Vaccination and Infection. Clin. Chem. (IF 12.167) Pub Date : 2022-07-27 Anda Bularga,Ellen Oskoui,Takeshi Fujisawa,Sara Jenks,Rachel Sutherland,Fred S Apple,Ola Hammarsten,Nicholas L Mills
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Commentary on Macrotroponin Complex as a Cause for Cardiac Troponin Increase after COVID-19 Vaccination and Infection. Clin. Chem. (IF 12.167) Pub Date : 2022-07-27 Peter A Kavsak
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Commentary on Macrotroponin Complex as a Cause for Cardiac Troponin Increase after COVID-19 Vaccination and Infection. Clin. Chem. (IF 12.167) Pub Date : 2022-07-27 Bernard Croal
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CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-26 Dongzheng Gai,Jin-Ran Chen,James P Stewart,Intawat Nookaew,Hasem Habelhah,Cody Ashby,Fumou Sun,Yan Cheng,Can Li,Hongwei Xu,Bailu Peng,Tarun K Garg,Carolina Schinke,Sharmilan Thanendrarajan,Maurizio Zangari,Fangping Chen,Bart Barlogie,Frits van Rhee,Guido Tricot,John D Shaughnessy,Fenghuang Zhan
Osteolytic bone disease is a hallmark of multiple myeloma (MM). A significant fraction (~20%) of MM patients do not develop osteolytic lesions (OL). The molecular basis for the absence of bone disease in MM is not understood. We combined PET-CT and gene expression profiling (GEP) of purified bone marrow (BM) CD138+ MM cells from 512 newly diagnosed MM patients to reveal that elevated expression of
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Commentary on Questionable High Free T4 Concentrations: When Confirming against an Alternative Method Is Not Enough. Clin. Chem. (IF 12.167) Pub Date : 2022-07-23 Robert D Nerenz
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Clinical Validation of Genome Reference Consortium Human Build 38 in a Laboratory Utilizing Next-Generation Sequencing Technologies Clin. Chem. (IF 12.167) Pub Date : 2022-07-23 Lisa A Lansdon, Maxime Cadieux-Dion, John C Herriges, Jeffrey Johnston, Byunggil Yoo, Joseph T Alaimo, Isabelle Thiffault, Neil Miller, Ana S A Cohen, Elena A Repnikova, Lei Zhang, Midhat S Farooqi, Emily G Farrow, Carol J Saunders
Background Laboratories utilizing next-generation sequencing align sequence data to a standardized human reference genome (HRG). Several updated versions, or builds, have been released since the original HRG in 2001, including the Genome Reference Consortium Human Build 38 (GRCh38) in 2013. However, most clinical laboratories still use GRCh37, which was released in 2009. We report our laboratory’s
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Isoniazid and rifapentine treatment effectively reduces persistent M. tuberculosis infection in macaque lungs. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-21 Riti Sharan,Shashank R Ganatra,Dhiraj K Singh,Journey Cole,Taylor W Foreman,Rajesh Thippeshappa,Charles A Peloquin,Vinay Shivanna,Olga Gonzalez,Cheryl L Day,Neel R Gandhi,Edward J Dick,Shannan Hall-Ursone,Smriti Mehra,Larry S Schlesinger,Jyothi Rengarajan,Deepak Kaushal
Once-weekly oral dose of isoniazid and rifapentine for 12 weeks (3HP) is recommended by CDC for treatment of latent tuberculosis infection (LTBI). The aim of this study is to assess 3HP-mediated clearance of Mtb bacteria in macaques with asymptomatic LTBI. Twelve Indian rhesus macaques were infected with low dose (~10 CFU) of Mtb CDC1551 via aerosol. Six animals were treated with 3HP and six were left
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Herpes simplex virus lymphadenitis is associated with tumor reduction in a chronic lymphocytic leukemia patient. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-21 Andres Chang,Anton M Sholukh,Andreas Wieland,David L Jaye,Mary Carrington,Meei-Li Huang,Hong Xie,Keith R Jerome,Pavitra Roychoudhury,Alexander L Greninger,Jean L Koff,Jonathon B Cohen,David M Koelle,Lawrence Corey,Christopher R Flowers,Rafi Ahmed
BACKGROUND Herpes simplex virus lymphadenitis (HSVL) is an unusual presentation of HSV reactivation in chronic lymphocytic leukemia (CLL) patients characterized by systemic symptoms and no herpetic lesions. The immune responses during HSVL have not been studied. METHODS Peripheral blood and lymph node samples of a patient with HSVL were obtained. HSV-2 viral load, antibody levels, B and T cell responses
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Recovery Efficiency of Cell-Free DNA After Bisulfite Conversion. Clin. Chem. (IF 12.167) Pub Date : 2022-07-20 Teagan Fisher,Caroline E Ford,Kristina Warton
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An optimized bicistronic chimeric antigen receptor against GPC2 or CD276 overcomes heterogeneous expression in neuroblastoma. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-19 Meijie Tian,Adam T Cheuk,Jun S Wei,Abdalla Abdelmaksoud,Hsien-Chao Chou,David Milewski,Michael C Kelly,Young K Song,Christopher M Dower,Nan Li,Haiying Qin,Yong Yean Kim,Jerry T Wu,Xinyu Wen,Mehdi Benzaoui,Katherine E Masih,Xiaolin Wu,Zhongmei Zhang,Sherif Badr,Naomi Taylor,Brad St Croix,Mitchell Ho,Javed Khan
Chimeric antigen receptor (CAR) T-cell therapies targeting single antigens perform poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated antigens (TAAs), limited T-cell persistence and exhaustion. Here we aimed to identify optimal CARs against Glypican-2 (GPC2) or CD276 (B7-H3), which were highly but heterogeneously expressed in neuroblastoma (NB), a lethal extracranial
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Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic therapeutic viruses. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-19 Juan Yan,Yuedan Chen,Amish J Patel,Sarah Warda,Cindy J Lee,Briana G Nixon,Elissa Wp Wong,Miguel A Miranda-Román,Ning Yang,Yi Wang,Mohini R Pachai,Jessica Sher,Emily Giff,Fanying Tang,Ekta Khurana,Samuel Singer,Yang Liu,Phillip M Galbo,Jesper Lv Maag,Richard P Koche,Deyou Zheng,Cristina Antonescu,Liang Deng,Ming Li,Yu Chen,Ping Chi
Immune checkpoint blockade (ICB) has demonstrated clinical success in "inflamed" tumors with substantial T-cell infiltrates, but tumors with an immune-desert tumor microenvironment (TME) fail to benefit. The tumor cell-intrinsic molecular mechanisms of the immune-desert phenotype remain poorly understood. Here, we demonstrated that inactivation of the Polycomb-repressive complex 2 (PRC2) core components
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Human midbrain dopaminergic neuronal differentiation markers predict cell therapy outcomes in a Parkinson’s disease model J. Clin. Invest. (IF 19.456) Pub Date : 2022 Peibo Xu, Hui He, Qinqin Gao, Yingying Zhou, Ziyan Wu, Xiao Zhang, Linyu Sun, Gang Hu, Qian Guan, Zhiwen You, Xinyue Zhang, Wenping Zheng, Man Xiong, Yuejun Chen
Human pluripotent stem cell–based (hPSC-based) replacement therapy holds great promise for the treatment of Parkinson’s disease (PD). However, the heterogeneity of hPSC-derived donor cells and the low yield of midbrain dopaminergic (mDA) neurons after transplantation hinder its broad clinical application. Here, we have characterized the single-cell molecular landscape during mDA neuron differentiation
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Stepwise GATA1 and SMC3 mutations alter megakaryocyte differentiation in a Down syndrome leukemia model J. Clin. Invest. (IF 19.456) Pub Date : 2022 Brahim Arkoun, Elie Robert, Fabien Boudia, Stefania Mazzi, Virginie Dufour, Aurélie Siret, Yasmine Mammasse, Zakia Aid, Matthieu Vieira, Imanci Aygun, Marine Aglave, Marie Cambot, Rachel Petermann, Sylvie Souquere, Philippe Rameau, Cyril Catelain, Romain Diot, Gérard Tachdjian, Olivier Hermine, Nathalie Droin, Najet Debili, Isabelle Plo, Sébastien Malinge, Eric Soler, Hana Raslova, Thomas Mercher,
Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modeled the megakaryocyte differentiation defect through stepwise gene editing of GATA1s, SMC3+/–, and MPLW515K, providing 20 different T21 or
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Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model J. Clin. Invest. (IF 19.456) Pub Date : 2022 Rhona McGonigal, Clare I. Campbell, Jennifer A. Barrie, Denggao Yao, Madeleine E. Cunningham, Colin L. Crawford, Simon Rinaldi, Edward G. Rowan, Hugh J. Willison
In Guillain-Barré syndrome (GBS), both axonal and demyelinating variants can be mediated by complement-fixing anti–GM1 ganglioside autoantibodies that target peripheral nerve axonal and Schwann cell (SC) membranes, respectively. Critically, the extent of axonal degeneration in both variants dictates long-term outcome. The differing pathomechanisms underlying direct axonal injury and the secondary bystander
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Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer J. Clin. Invest. (IF 19.456) Pub Date : 2022 Siqi Chen, Ping Xie, Matthew Cowan, Hao Huang, Horacio Cardenas, Russell Keathley, Edward J. Tanner, Gini F. Fleming, John W. Moroney, Alok Pant, Azza M. Akasha, Ramana V. Davuluri, Masha Kocherginsky, Bin Zhang, Daniela Matei
Background. Immune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC). To augment their activity, we used priming with the hypomethylating agent guadecitabine in a phase II study.
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A Shigella species variant is causally linked to intractable functional constipation J. Clin. Invest. (IF 19.456) Pub Date : 2022 Xin Chen, Tian-Tian Qiu, Ye Wang, Li-Yang Xu, Jie Sun, Zhi-Hui Jiang, Wei Zhao, Tao Tao, Yu-Wei Zhou, Li-Sha Wei, Ye-Qiong Li, Yan-Yan Zheng, Guo-Hua Zhou, Hua-Qun Chen, Jian Zhang, Xiao-Bo Feng, Fang-Yu Wang, Ning Li, Xue-Na Zhang, Jun Jiang, Min-Sheng Zhu
Intractable functional constipation (IFC) is the most severe form of constipation, but its etiology has long been unknown. We hypothesized that IFC is caused by refractory infection by a pathogenic bacterium. Here, we isolated from patients with IFC a Shigella species — peristaltic contraction–inhibiting bacterium (PIB) — that significantly inhibited peristaltic contraction of the colon by production
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Myeloid FoxO1 depletion attenuates hepatic inflammation and prevents nonalcoholic steatohepatitis J. Clin. Invest. (IF 19.456) Pub Date : 2022 Sojin Lee, Taofeek O. Usman, Jun Yamauchi, Goma Chhetri, Xingchun Wang, Gina M. Coudriet, Cuiling Zhu, Jingyang Gao, Riley McConnell, Kyler Krantz, Dhivyaa Rajasundaram, Sucha Singh, Jon Piganelli, Alina Ostrowska, Alejandro Soto-Gutierrez, Satdarshan P. Monga, Aatur D. Singhi, Radhika Muzumdar, Allan Tsung, H. Henry Dong
Hepatic inflammation is culpable for the evolution of asymptomatic steatosis to nonalcoholic steatohepatitis (NASH). Hepatic inflammation results from abnormal macrophage activation. We found that FoxO1 links overnutrition to hepatic inflammation by regulating macrophage polarization and activation. FoxO1 was upregulated in hepatic macrophages, correlating with hepatic inflammation, steatosis, and
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Can Rapid Nanopore Sequencing Bring Genomic Testing to the Bedside? Clin. Chem. (IF 12.167) Pub Date : 2022-07-15 Sebastian Lunke,Zornitza Stark
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Frequent detection but lack of infectivity of SARS-CoV-2 RNA in pre-symptomatic, infected blood donor plasma. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-14 Paula Saá,Rebecca V Fink,Sonia Bakkour,Jing Jin,Graham Simmons,Marcus O Muench,Hina Dawar,Clara Di Germanio,Alvin J Hui,David J Wright,David E Krysztof,Steven H Kleinman,Angela Cheung,Theresa Nester,Debra A Kessler,Rebecca L Townsend,Bryan R Spencer,Hany Kamel,Jacquelyn M Vannoy,Honey Dave,Michael P Busch,Susan L Stramer,Mars Stone,Rachael P Jackman,Philip J Norris
Respiratory viruses such as influenza do not typically cause viremia; however, SARS-CoV-2 has been detected in the blood of COVID-19 patients with mild and severe symptoms. Detection of SARS-CoV-2 in blood raises questions about its role in pathogenesis as well as transfusion safety concerns. Blood donor reports of symptoms or a diagnosis of COVID-19 after donation (post-donation information, PDI)
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Host-versus-commensal immune responses participate in the rejection of colonized solid organ transplants. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-14 Isabella D Pirozzolo,Martin Sepulveda,Luqiu Chen,Ying Wang,Yuk Man Lei,Zhipeng Li,Rena Li,Husain Sattar,Betty R Theriault,Yasmine Belkaid,Anita S Chong,Maria-Luisa Alegre
Solid organ transplantation is the preferred treatment for end-stage organ failure. Although transplant recipients takelife-long immunosuppressive drugs, a substantial percentage of them still reject their allografts. Strikingly, barrier organs colonized with microbiota have significantly shorter half-lives than non-barrier transplanted organs, even in immunosuppressed hosts. We previously demonstrated
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Human-β-defensin-3 attenuates atopic dermatitis-like inflammation through autophagy activation and the aryl hydrocarbon receptor signaling pathway. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-14 Ge Peng,Saya Tsukamoto,Risa Ikutama,Hai Le Thanh Nguyen,Yoshie Umehara,Juan V Trujillo-Paez,Hainan Yue,Miho Takahashi,Takasuke Ogawa,Ryoma Kishi,Mitsutoshi Tominaga,Kenji Takamori,Jiro Kitaura,Shun Kageyama,Masaaki Komatsu,Ko Okumura,Hideoki Ogawa,Shigaku Ikeda,François Niyonsaba
Human-β-defensin (hBD)-3 exhibits antimicrobial and immunomodulatory activities; however, its contribution to autophagy regulation remains unclear, and the role of autophagy in the regulation of the epidermal barrier in atopic dermatitis (AD) is poorly understood. Here, keratinocyte autophagy was restrained in the skin lesions of patients with AD and murine models of AD. Interestingly, hBD-3 alleviated
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Genome-wide DNA hypermethylation opposes healing in chronic wound patients by impairing epithelial-to-mesenchymal transition. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-12 Kanhaiya Singh,Yashika Rustagi,Ahmed S Abouhashem,Saba Tabasum,Priyanka Verma,Edward Hernandez,Durba Pal,Dolly K Khona,Sujit K Mohanty,Manishekhar Kumar,Rajneesh Srivastava,Poornachander R Guda,Sumit S Verma,Sanskruti Mahajan,Jackson A Killian,Logan A Walker,Subhadip Ghatak,Shomita S Mathew-Steiner,Kristen Wanczyk,Sheng Liu,Jun Wan,Pearlly Yan,Ralf Bundschuh,Savita Khanna,Gayle M Gordillo,Michael P
An extreme chronic wound tissue microenvironment causes epigenetic gene silencing. Unbiased whole-genome methylome was studied in the wound-edge (WE) tissue of chronic wound patients. A total of 4689 differentially methylated regions (DMRs) were identified in chronic WE compared to unwounded (UW) human skin. Hypermethylation was more frequently observed (3661 DMRs) in the chronic WE compared to hypomethylation
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Hematopoietic transcription factor GFI1 promotes anchorage independence by sustaining ERK activity in cancer cells. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-12 Hao Wang,Zhenzhen Lin,Zhe Nian,Wei Zhang,Wenxu Liu,Fei Yan,Zengtuan Xiao,Xia Wang,Zhenfa Zhang,Zhenyi Ma,Zhe Liu
The switch from anchorage-dependent to anchorage-independent growth is essential for epithelial metastasis. The underlying mechanism, however, is not fully understood. Here in this study, we identified growth factor independent-1 (GFI1), a transcription factor that drives transition from adherent endothelial cells to suspended hematopoietic cells during hematopoiesis, as a critical regulator of an
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Estimating Analytical Errors of Glomerular Filtration Rate Measurement Clin. Chem. (IF 12.167) Pub Date : 2022-07-08 Damiano Ognissanti, Moa Andresen Bergström, Elvar Theodorsson, Anders Larsson, Gunnar Nordin, Ola Hammarsten
Background Few studies are available on how to optimize time points for sampling and how to estimate effects of analytical uncertainty when glomerular filtration rate (GFR) is calculated. Methods We explored the underlying regression mathematics of how analytical variation of a kidney filtration marker affects 1-compartment, slope-and-intercept GFR calculations, using 2 or 3 time points following a
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Integrated hepatitis B virus DNA maintains surface antigen production during antivirals. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-07 Tanner Grudda,Hyon S Hwang,Maraake Taddese,Jeffrey Quinn,Mark S Sulkowski,Richard K Sterling,Ashwin Balagopal,Chloe L Thio
The focus of hepatitis B functional cure, defined as sustained loss of hepatitis B surface antigen (HBsAg) and HBV DNA from blood, is on eliminating or silencing the intranuclear template for HBV replication, covalently closed circular DNA (cccDNA). However, HBsAg also derives from HBV DNA integrated into the host genome (iDNA). Little is known about the contribution of iDNA to circulating HBsAg with
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Harmonization Status of Serum Ferritin Measurements and Implications for Use as Marker of Iron-Related Disorders Clin. Chem. (IF 12.167) Pub Date : 2022-07-07 Federica Braga, Sara Pasqualetti, Erika Frusciante, Francesca Borrillo, Mariia Chibireva, Mauro Panteghini
Background Serum ferritin is considered a suitable biomarker of iron-related disorders. However, data about the comparability of results among commercial measuring systems (MSs) are contradictory. We performed an intercomparison study aimed at verifying the current interassay variability and its impact on clinical application of the test. Obtaining this information is vital because manufacturers continue
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Tetracycline-induced mitohormesis mediates disease tolerance against influenza. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-05 Adrienne Mottis,Terytty Y Li,Gaby El Alam,Alexis Rapin,Elena Katsyuba,David Liaskos,Davide D'Amico,Nicola L Harris,Mark C Grier,Laurent Mouchiroud,Mark L Nelson,Johan Auwerx
Mitohormesis defines the increase in fitness mediated by adaptive responses to mild mitochondrial stress. Tetracyclines inhibit not only bacterial but also mitochondrial translation, thus imposing a low level of mitochondrial stress to eukaryotic cells. We demonstrate in cell and germ-free mouse models, that tetracyclines induce a mild adaptive mitochondrial stress response (MSR), involving both the
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LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade J. Clin. Invest. (IF 19.456) Pub Date : 2022 Amber Hickman, Joost Koetsier, Trevin Kurtanich, Michael C. Nielsen, Glenn Winn, Yunfei Wang, Salah-Eddine Bentebibel, Leilei Shi, Simone Punt, Leila Williams, Cara Haymaker, Charles B. Chesson, Faisal Fa’ak, Ana L. Dominguez, Richard Jones, Isere Kuiatse, Amy R. Caivano, Sayadeth Khounlo, Navin D. Warier, Upendra Marathi, Robert V. Market, Ronald J. Biediger, John W. Craft Jr., Patrick Hwu, Michael
The inability of CD8+ effector T cells (Teffs) to reach tumor cells is an important aspect of tumor resistance to cancer immunotherapy. The recruitment of these cells to the tumor microenvironment (TME) is regulated by integrins, a family of adhesion molecules that are expressed on T cells. Here, we show that 7HP349, a small-molecule activator of lymphocyte function–associated antigen-1 (LFA-1) and
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The Achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence J. Clin. Invest. (IF 19.456) Pub Date : 2022 Shameel Shafqat, Evelyn Arana Chicas, Areez Shafqat, Shahrukh K. Hashmi
Recent improvements in cancer treatment have increased the lifespan of pediatric and adult cancer survivors. However, cancer treatments accelerate aging in survivors, which manifests clinically as the premature onset of chronic diseases, such as endocrinopathies, osteoporosis, cardiac dysfunction, subsequent cancers, and geriatric syndromes of frailty, among others. Therefore, cancer treatment–induced
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miR-181b targets semaphorin 3A to mediate TGF-β–induced endothelial-mesenchymal transition related to atrial fibrillation J. Clin. Invest. (IF 19.456) Pub Date : 2022 Ying-Ju Lai, Feng-Chun Tsai, Gwo-Jyh Chang, Shang-Hung Chang, Chung-Chi Huang, Wei-Jan Chen, Yung-Hsin Yeh
Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition (EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-β–treated human AEECs, cardiac-specific TGF-β–transgenic mice, and heart failure rabbits to identify the underlying mechanism of
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Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma J. Clin. Invest. (IF 19.456) Pub Date : 2022 Patrick C. Lee, Susan Klaeger, Phuong M. Le, Keegan Korthauer, Jingwei Cheng, Varsha Ananthapadmanabhan, Thomas C. Frost, Jonathan D. Stevens, Alan Y.L. Wong, J. Bryan Iorgulescu, Anna Y. Tarren, Vipheaviny A. Chea, Isabel P. Carulli, Camilla K. Lemvigh, Christina B. Pedersen, Ashley K. Gartin, Siranush Sarkizova, Kyle T. Wright, Letitia W. Li, Jason Nomburg, Shuqiang Li, Teddy Huang, Xiaoxi Liu, Lucas
Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I–low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of
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RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis J. Clin. Invest. (IF 19.456) Pub Date : 2022 Jonathan Shintaku, Wolfgang M. Pernice, Wafaa Eyaid, Jeevan B. GC, Zuben P. Brown, Marti Juanola-Falgarona, Javier Torres-Torronteras, Ewen W. Sommerville, Debby M.E.I. Hellebrekers, Emma L. Blakely, Alan Donaldson, Ingrid van de Laar, Cheng-Shiun Leu, Ramon Marti, Joachim Frank, Kurenai Tanji, David A. Koolen, Richard J. Rodenburg, Patrick F. Chinnery, H.J.M. Smeets, Gráinne S. Gorman, Penelope E
Mitochondrial DNA (mtDNA) depletion/deletions syndromes (MDDS) encompass a clinically and etiologically heterogenous group of mitochondrial disorders caused by impaired mtDNA maintenance. Among the most frequent causes of MDDS are defects in nucleoside/nucleotide metabolism, which is critical for synthesis and homeostasis of the deoxynucleoside triphosphate (dNTP) substrates of mtDNA replication. A
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Specific in situ inflammatory states associate with progression to renal failure in lupus nephritis J. Clin. Invest. (IF 19.456) Pub Date : 2022 Rebecca Abraham, Madeleine S. Durkee, Junting Ai, Margaret Veselits, Gabriel Casella, Yuta Asano, Anthony Chang, Kichul Ko, Charles Oshinsky, Emily Peninger, Maryellen L. Giger, Marcus R. Clark
BACKGROUND. In human lupus nephritis (LN), tubulointerstitial inflammation (TII) on biopsy predicts progression to end-stage renal disease (ESRD). However, only about half of patients with moderate-to-severe TII develop ESRD. We hypothesized that this heterogeneity in outcome reflects different underlying inflammatory states. Therefore, we interrogated renal biopsies from LN longitudinal and cross-sectional
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Lymphocytes in the neighborhood: good or bad for the kidney? J. Clin. Invest. (IF 19.456) Pub Date : 2022 Hao Li, Maria G. Tsokos, George C. Tsokos
Lupus nephritis (LN) is common in people with systemic lupus erythematosus (SLE) and advances, almost invariably, to end-stage renal disease (ESRD). In this issue of the JCI, Abraham, Durkee, et al. presented a large-scale immune cell landscape of kidney biopsies from patients with LN by combining multiplexed confocal microscopy imaging with customized computer vision and quantification. The presence
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TGF-β1–induced endothelial-mesenchymal transition: a potential contributor to fibrotic remodeling in atrial fibrillation? J. Clin. Invest. (IF 19.456) Pub Date : 2022 Arnela Saljic, Eleonora Grandi, Dobromir Dobrev
Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with an unmet therapeutic need. Fibrotic remodeling, in which collagen-producing atrial fibroblasts play a crucial role, substantially contributes to arrhythmia promotion and progression. In this issue of the JCI, Lai, Tsai, and co-authors reveal that TGF-β1 promoted endothelial-mesenchymal transition during AF and put forward